Developmental perturbation of Purkinje cell function induces male-biased core and associated autism spectrum disorder–like phenotypes in adulthood

Abstract Autism spectrum disorder (ASD) is a prevalent neurodevelopmental condition whose etiology remains incompletely understood. Human epidemiological studies have implicated the cerebellum in ASD pathogenesis, and studies in mouse models have provided evidence for a causal contribution of cerebellar dysfunction. However, previous animal studies have largely focused on males and cerebellar manipulations at later developmental stages, with associated features of ASD remaining less explored. To address these gaps, we chemogenetically perturbed Purkinje cell function during early postnatal development in both male and female mice. Developmental Purkinje cell perturbation induced male-biased core ASD-like behavioral phenotypes, including reduced sociability and cognitive inflexibility. Phenotypes related to associated features of ASD, including impaired fine motor learning, altered sensory processing, and sleep abnormalities, were also predominantly observed in males. At the molecular level, bulk RNA sequencing following developmental Purkinje cell perturbation identified candidate sex-dependent transcriptional changes in both the hindbrain and forebrain, suggesting that altered cerebellar activity during development can influence gene expression across distant brain regions. Together, these findings demonstrate that transient early postnatal perturbation of Purkinje cell function can produce diverse core and associated ASD-like phenotypes, predominantly in males, with evidence suggesting transcriptional changes beyond the cerebellum. This study highlights developmental cerebellar dysfunction as a potential contributor to sex differences in ASD vulnerability.